PHYSIOLOGICAL REVIEWS
Vol. 80, No. 4, October 2000
Printed in U.S.A.
Role of Platelet-Activating Factor
in Cardiovascular Pathophysiology
GIUSEPPE MONTRUCCHIO, GIUSEPPE ALLOATTI, AND GIOVANNI CAMUSSI
Laboratorio di Immunopatologia Renale, Dipartimento di Medicina Interna, Dipartimento di Biologia Animale
e dell’Uomo e Istituto Nazionale di Fisica della Materia, Università di Torino, Torino, Italy
I. Introduction
II. Molecular Heterogeneity of Platelet-Activating Factor and Functional Implications
III. Metabolism of Platelet-Activating Factor
A. PAF biosynthetic pathways
B. PAF catabolism
IV. Platelet-Activating Factor Receptors and Signal Transduction
V. Cardiovascular Responses to Platelet-Activating Factor
A. Hemodynamic effect of PAF
B. Effect of local administration of PAF on selected vascular districts
VI. Effect of Platelet-Activating Factor on the Heart
A. Coronary circulation: in vivo effects
B. In vitro effects on isolated perfused heart
C. Myocardial function
D. Atrium and papillary muscle
E. Effects on cardiomyocytes
VII. Microvascular Effect of Platelet-Activating Factor In Vivo
VIII. Effects of Platelet-Activating Factor on Endothelial Cells
A. Effect of PAF on endothelial cell permeability
B. Endothelium-leukocyte and -platelet interaction
IX. Involvement of Platelet-Activating Factor in Cardiovascular Pathophysiological Processes
A. Role of PAF in cardiac anaphylaxis and shock syndromes
B. Role of PAF in ischemia-reperfusion injury of the heart
C. Role of PAF in atherogenesis
X. Role of Platelet-Activating Factor in Neoangiogenesis
XI. Conclusions
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Montrucchio, Guiseppe, Guiseppe Alloatti, and Giovanni Camussi. Role of Platelet-Activating Factor in
Cardiovascular Pathophysiology. Physiol Rev 80: 1669 –1699, 2000.—Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts
via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase
C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system.
The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved
in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it
stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood
pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the
hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF
has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the
recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to
the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular
pathophysiology.
http://physrev.physiology.org
0031-9333/00 $15.00 Copyright © 2000 the American Physiological Society
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I. INTRODUCTION
Platelet-activating factor (PAF) is one of the most
potent and versatile mediators found in mammals. It was
originally described as “a soluble factor” involved in leukocyte-dependent histamine and serotonin release from
platelets (177, 379). In 1972, Benveniste et al. (31) demonstrated that this soluble factor was released from rabbit
basophils after IgE stimulation and coined the term PAF.
Several reports followed describing the lipid nature of
PAF (29, 32, 113, 332). Almost concomitantly, a factor
with properties similar to PAF was isolated from the renal
medulla by Muirhead and co-workers (44, 303, 305). This
factor was named antihypertensive polar renal lipid because of its ability to lower blood pressure in the Goldblatt rat model of hypertension. In 1979, three independent groups (33, 44, 113) demonstrated that a semisynthetic phosphoacylglycerol, 1-O-alkyl-2-acetyl-sn-glycero3-phosphocholine, had physicochemical as well as biological properties indistinguishable from those of naturally occurring PAF/antihypertensive polar renal lipid.
Hanahan et al. (164) characterized by gas-liquid chromatography and mass spectral analysis the chemical structure of PAF released by IgE-sensitized rabbit basophils as
a 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. Although PAF continues to be the common term used, it
is a misnomer, because it identifies only the platelet
effect of this mediator. PAF is now considered a phospholipid with diverse and potent physiological effects
that belongs to a family of biologically active, structurally related alkyl phosphoglycerides (48, 79, 100, 163,
280, 337, 384, 385, 442, 446). PAF is thought to be a
mediator of cell-to-cell communication, which may
function either as an intercellular or an intracellular
messenger (100). Some of its actions are achieved at
concentrations as low as 10⫺12 M and include events
relevant for the development of several pathological
and physiological processes. Numerous cell types and
tissues have been shown to produce PAF upon appropriate stimulation (47). In particular, PAF is produced
by a variety of cells that may participate in the development of inflammatory reaction such as monocytes/
macrophages, polymorphonuclear neutrophils (PMN),
eosinophils, basophils, and platelets (50, 79, 260, 428).
In addition, human endothelial cells were found to
produce PAF after stimulation by several inflammatory
mediators (458) including thrombin (69, 179, 336, 474),
angiotensin II (69), vasopressin (69), leukotrienes C4
and D4 (276), histamine (276), bradykinin (276), elastase (80), cathepsin G (80), hydrogen peroxide (145,
255), plasmin (289, 298), interleukin (IL)-8 (21) and
IL-1␣, or tumor necrosis factor (TNF)-␣ (61, 64, 60, 73,
228, 229, 286). Cardiomyocytes have been also reported
to synthesize PAF under appropriate stimulation (200).
Most of the cells that produce PAF also possess PAF
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receptors (185, 232, 403, 470) and are target for PAF
action. In vitro, PAF promotes the aggregation, chemotaxis, granule secretion, and oxygen radical generation
from leukocytes and the adherence of leukocytes to the
endothelium (51, 81, 322, 373, 480). PAF increases the
permeability of endothelial cell monolayer (62), stimulates the contraction of smooth muscle (139, 209, 396)
and myometrium (292, 414), and has negative inotropic,
arrhythmogenic effects on cardiac muscle (11, 30, 71,
251, 352, 353).
In this paper we review the molecular and cellular
basis for the structural and functional diversity of PAF
molecules, the different biosynthetic and catabolic pathways of PAF, and the signal transduction triggered by the
engagement of PAF receptor. Moreover, we describe the
systemic and local effects of PAF administration in vivo
and the mechanical and electrophysiological effects of
PAF on isolated perfused heart, atrium, and papillary
muscle and on cultured cardiomyocytes. We also examine
the microcirculatory effect of PAF and its role in the
interaction between endothelial and inflammatory cells.
Finally, the involvement of PAF in cardiovascular pathophysiological processes such as shock syndromes, ischemia-reperfusion injury, atherogenesis, and neoangiogenesis is discussed in the light of the biological properties of
this mediator and of the effect of PAF-receptor antagonists.
II. MOLECULAR HETEROGENEITY
OF PLATELET-ACTIVATING FACTOR
AND FUNCTIONAL IMPLICATIONS
Although PAF is generally considered as a single
molecular entity with a wide spectrum of diverse and
potent biological properties, it is now clear that there
are a variety of structurally related phospholipid molecules of biological origin that share many of the same
physiological activities (for review, see Ref. 280). However, the chemical structure strictly influences the biological potency of PAF (384). The full expression of its
biological potency requires an ether linkage at the sn-1
position of the glycerol backbone, a short acyl chain,
usually an acetyl residue, at the sn-2 position, and the
polar head group of choline or ethanolamine at the sn-3
position (280, 384). The length of the alkyl chain at the
sn-1 position and the number of double bonds have
modest effects on its biological potency. In contrast,
the presence of an esther linkage at the sn-1 position of
glycerol or a three-carbons longer acyl chain at sn-2
position significantly diminishes and changes the biological properties. Mass spectral analysis of PAF synthesized by human PMN showed the presence of multiple molecular species of alkyl PAF including 15:0-,
16:0-, 17:0-branched chain, 17:0-, 18:0-, 18:1-, 18:2-, and
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PAF AND THE CARDIOVASCULAR SYSTEM
22:2-PAF (262, 333, 452, 453). Human PMN also produce
acyl-PAF that represents 13–25% of total PAF synthesized by these cells (301, 426). More recently, it has
been suggested that the acyl-PAF may be the major
molecular species of PAF produced by several cell
types including human pulmonary mastocytes (425,
427) and vascular endothelium (104, 428, 457). Perfused
rat and guinea pig hearts (312) produce vinyl-PAF.
Other species of biologically active acetylated glycerolipids are the plasmalogen analogs of PAF such as
1-alk-1⬘-enyl-2-acetyl-sn-glycero-3-phosphocholine and
1-alk-1⬘-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine
and the 1-alkyl-2-acetyl-sn-glycerols, the neutral lipid
precursor of PAF. Such plasmalogens even if less active
than PAF itself can act synergistically with PAF (262,
385). The biological activities of 1-alkyl-2-acetyl-snglycerols have been related to the conversion of these
neutral lipids to PAF. However, 1-alkyl-2-acetyl-sn-glycerols and their metabolic products have been shown to
possess intrinsic biological activities (437) including
differentiation of HL-60 cells (281), attenuation of diacylglycerol-induced activation of protein kinase C
(PKC), and activation of macrophages (466). Finally,
the 1-alkyl-2-acetyl-sn-glycero-phosphate, an analog of
phosphatidic acid, can act as a calcium ionophore (63).
The different molecular species of PAF have different
potency on platelet activation (280). However, platelet
bioassay does not necessarily reflect the biological potential of a given molecular species on other cell types
or tissues. For instance, it has been shown that the
presence of a single double bond in the alkyl chain at
the sn-1 position significantly alters the cardiac activity
by increasing 50-fold the negative inotropism and 100fold coronary vasoconstriction but has little effect on
the stimulation of platelets (280). McManus et al. (280)
have recently reviewed the differences in the rank orders of potency of alkyl and acyl-PAF molecules in vitro
on rabbit platelets, human PMN, and isolated guinea pig
heart, and in vivo, when injected into rabbit on thrombocytopenia, leukopenia, and right ventricular hypertension. It has been suggested that the differences in
the biological properties of various molecular species
of PAF may depend on differences in the biophysical
properties as critical micellar concentration or albumin
binding affinity or on the existence of more than one
receptor subtype for PAF.
III. METABOLISM OF PLATELET-ACTIVATING
FACTOR
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PAF is synthesized by two main pathways in a
variety of tissues and cells. The “remodeling pathway”
is mainly involved in the synthesis of PAF by stimulated
inflammatory cells (14, 240, 319). This pathway requires
a tightly coupled reaction of phospholipase (PL) A2 and
acetyl CoA:1-alkyl-sn-glycero-3-phosphorylcholine 2-Oacetyltransferase (464). The activation of PLA2 (461)
determines the hydrolysis of membrane phospholipids
to generate a variety of 2-lysophospholipids (e.g., 1-alkyl-2-lyso-glycero-3-phosphocholine, lyso-PAF). These
2-lysophospholipids are the substrate of acetyl CoA:1alkyl-sn-glycero-3-phosphorylcholine 2-O-acetyltransferase, which catalyzes the transfer of the acetyl moiety
from acetyl CoA to the free hydroxyl at sn-2 position. In
addition to a direct deacylation of membrane glycerophospholipids, another pathway for the generation of
2-lysophospholipids has been recently described. Indeed, lyso-PAF can be obtained via a CoA-independent
transacylation reaction between alkylacyl-glycerol-3phosphocholine and the lysophospholipid acceptor
formed via the action of a putative PLA2 (25, 106, 317,
386, 434, 445). This CoA-independent transacylase
route accounts for the simultaneous PAF synthesis and
mobilization of arachidonic acid, since it is specific for
the arachidonate linked species of alkyl choline phosphoglycerides (354, 460). Figure 1 shows the enzymatic
steps of the remodeling pathway.
The second biosynthetic pathway of PAF that is
mainly operative in the kidney and in the central nervous
system (65, 350, 384) has been termed “de novo pathway”
(Fig. 2). This involves the synthesis of 1-O-alkyl-2-acetylglycerol, which is then converted to PAF by a specific
dithiothreitol-insensitive CDP-choline:1-alkyl-2-acetyl-snglycerol cholinephosphotransferase. Except for the insensitivity of cholinephosphotransferase to dithiothreitol,
this pathway is analogous to that involved in the biosynthesis of lecithins (350). The direct precursors of PAF in
this pathway are 1-alkyl-2-acetyl-sn-glycerols, formed via
an acetylation-dephosphorylation sequence, which is catalyzed by acetyl CoA:1-alkyl-2-lyso-sn-glycero-3-phosphate acetyltransferase and by 1-alkyl-2-acetyl-sn-glycero3-phosphate phosphohydrolase (239, 243, 244).
The enzymes of the remodeling pathway and de novo
pathway have relative broad substrate specificities that
provide a basis for heterogeneity in the molecular species
of PAF produced by a given cell or tissue in response to
a specific stimulus (280, 384).
B. PAF Catabolism
A. PAF Biosynthetic Pathways
The molecular heterogeneity of PAF possibly depends on the multiple enzymatic steps involved in its
synthesis and degradation by different cell types.
The synthesis and catabolism of this potent phospholipid autacoid are highly regulated. The final molecular
composition of PAF in tissues and the expression of its
biological activities depend also on the activation of cat-
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receptors (382) and have been implicated in the pathogenesis of atherosclerosis (174). The lyso-PAF is then
reacylated by an acyl-CoA:1-radyl-sn-glycero-3-phosphorylcholine acyltransferase. The alkyl moiety of lyso-PAF is
known to be cleaved to an aldehyde by a tetrahydropiridine-dependent alkyl monooxygenase (239). Alternatively, phospholipase D can hydrolyze phosphocholine
moiety to produce an analog of phosphatidic acid or
catalyze a phosphatase transfer by a transphosphatidylation reaction (7). The acyl PAF molecule can be also
degraded by a PLA1, which hydrolyzes the long-chain fatty
acyl residue esterified at the sn-1 position to produce
1-lyso-2-acetyl-glycero-3-phosphocholine (424). Recently,
it has been shown that guinea pig hearts release acetyl
hydrolase in the systemic circulation and that isolated
ventricular myocytes are capable to take up PAF and
catabolize it to inactive products (341, 423). The coronary
artery bypass surgery has been shown to induce changes
in serum PAF-acetyl hydrolase activity (314).
FIG. 1. Remodeling pathways for synthesis of platelet-activating
factor (PAF). PAF synthesis is initiated by the activation of phospholipase A2 (PLA2), which may act on 1-O-alkyl-2-arachidonoyl glycerophosphocholine to yield lyso-PAF and free arachidonic acid. The lysoPAF is acetylated by a specific lyso-PAF acetyltransferase using acetyl
coenzyme A as a donor. Alternatively PLA2 may act on arachidonatecontaining plasmalogen phosphatidylethanolamine to release free arachidonate. The lyso-phosphatidylethanolamine may act as an acceptor
for arachidonate in a transacylation reaction from the PAF precursor
with formation of lyso-PAF. Therefore, the activation of PLA2 is essential for generation of lyso-PAF and triggering the remodeling pathways.
The activation of lyso-PAF acetyltransferase, which is modulated by a
phosphorylation/dephosphorylation cycle, is a limiting factor for generation of biologically active PAF.
abolic pathways. The most important enzyme in the limitation the PAF bioactivity is a PAF-specific acetylhydrolase (PAF-AH), which cleaves the short acyl chain at sn-2
position and forms the biologically inactive lyso-PAF.
This enzyme is present in plasma (130) and in various
tissues (43, 186, 242, 318, 392). The molecular cloning and
characterization of the human plasma PAF-AH have been
recently reported (415, 418). The PAF-AH activity found in
human plasma circulates as a complex with low- (LDL)
and high-density lipoproteins (HDL) (203, 391, 429). In
addition to the extracellular enzyme, the molecular characterization of two intracellular PAF-AH has been reported (171–173). PAF-AH degrades also PAF-like oxidized phospholipids that were shown to bind PAF
FIG. 2. De novo pathway for synthesis of PAF. In this pathway,
1-O-alchyl-sn-glycero-3-phosphate is acetylated by 1-O-alkyl-sn-glycero3-phosphate:acetyl CoA:acetyltranferase and is transformed by a specific phosphohydrolase into 1-O-alkyl-2-acetyl-sn-glycerol. The later is
then converted to PAF by a dithiothreitol-insensitive CDP-cholinephosphotransferase. This pathway is mainly involved in the constitutive
synthesis of PAF and is regulated only by the availability of substrates.
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PAF AND THE CARDIOVASCULAR SYSTEM
IV. PLATELET-ACTIVATING FACTOR
RECEPTORS AND SIGNAL TRANSDUCTION
PAF acts via specific receptors on the membranes of
responsive cells (38, 374) (Fig. 3). Binding studies revealed two distinct types of binding sites on human platelets (439). One binding site for PAF exhibited high affinity
with a dissociation constant (Kd) value of 37 ⫾ 13 nM and
had a low capacity of 1,399 ⫾ 498 sites/platelet. The
second binding site showed nearly infinite binding capacity with a low affinity for PAF. The activation of platelets
was due to the interaction of PAF with the high-affinity
binding sites. Rabbit platelets showed, as human platelets, high-affinity binding sites for PAF with a Kd of
0.9 ⫾ 0.5 nM (184, 372, 435). In contrast, rat platelets that
are insensitive to PAF action exhibited only the lowaffinity binding site for PAF (196, 313). It was subsequently shown that specific binding sites for PAF are
present in smooth muscle cells (193), cardiomyocytes
(403), neutrophils (321, 441), monocytes-macrophages
(257, 438), eosinophils (436), endothelial cells (223), and
Kupffer cells (94, 95, 97). Moreover, PAF specific binding
sites were identified in cells of the central nervous system. Three distinct classes of PAF binding sites have been
detected in synaptic plasma membranes and intracellular
membranes of rat cerebral cortex (121, 266, 416). Recently, it has been shown that PAF receptor in endothelial
cells is expressed not only on the cell surface but also in
the large endosomal compartment (195). The significance
of intracellular receptors has not yet been clarified. However, it has been suggested that intracellular PAF receptors may mediate a PAF-dependent signal transduction
pathway, as postulated for PAF-induced protooncogene
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expression (416). A cDNA for a PAF receptor from guinea
pig lung has been cloned (185). The strategy used involved the construction of a cDNA library from sidefractionated poly(A) RNA, the synthesis of a transcript of
the cDNA using phage DNA as template, and the expression of the transcript in the Xenopus oocytes (185). The
analysis of PAF receptor cDNA indicated that PAF receptor belongs to the family of “serpentine receptors,” which
contain seven ␣-helical domains that wave in and out of
the plasma membrane seven times. Surprisingly, PAF receptor contains only 342 amino acids and has a molecular
mass of 38,982 Da (185). The third intracellular loop and
the carboxyl tail, which is thought to bind G proteins in
the serpentine receptor family, are very short in PAF
receptor. It has been also found that there are nine potential phosphorylation sites on the carboxy end of the
receptor. Phosphorylation of the sites may modulate the
binding of G proteins to the receptors and may account
for the rapid desensitization of PAF receptors (310). Subsequently, PAF receptor was cloned from human leukocytes (232, 310) and HL-60 granulocytes (470). PAF receptor cloned from human leukocytes revealed 83% identity
in the amino acid sequence with that of guinea pig lung.
Recently, it has been shown that the PAF receptor protein
expressed by human cardiomyocytes is exactly the same
as that of human leukocytes (403). However, the 5⬘-noncoding region of cDNA encoding for cardiac PAF receptor
is different from that of leukocytes, suggesting the presence of a tissue-specific regulatory mechanism (403). The
induction of PAF receptor expression in Xenopus laevis
oocytes and in COS-7 cells shows that PAF receptor is
functionally linked to phosphoinositide metabolism by a
G protein (310). Although researchers believe that PAF is
FIG. 3. Schematic representation of
PAF receptor-signal transduction mechanisms. PLA2, phospholipase A2; G protein,
GTP-binding protein; PLC, phospholipase
C; PtdinsP2, phosphatidylinositol 4,5-bisphosphate; inositol-P2, inositol 4,5-bisphosphate; InsP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein
kinase C.
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MONTRUCCHIO, ALLOATTI, AND CAMUSSI
coupled to PLC and PLA2 through a G protein, the G
protein involved has not yet been fully characterized. It
has been suggested that PAF binds to receptor and activates the associated G protein by exchanging guanosine
triphosphate for guanosine diphosphate. In turn, the G
protein activates a phosphatidylinositol-specific PLC
(100). Therefore, stimulation of PAF receptors leads to
the transient production of diacylglycerol, which activates PKC, and of inositol trisphosphate, which mediates
the release of internal calcium stores. It has been proposed that the basic components of this pathway operate
in all cells bearing PAF receptors and that the different
responses to PAF depend on the function of target cells.
Moreover, PAF has been found to stimulate the release of
arachidonic acid in various cell types by different mechanisms (309, 311, 334, 449, 472). For instance, in neutrophils, PAF induces the activation of PLA2 by a mechanism
requiring only the mobilization of intracellular calcium
stores while in Kupffer cells PLA2 activation is dependent
on extracellular calcium influx (95). In addition, the activation of PLA2 by PAF occurs through a PKC-dependent
mechanism (96, 277, 320) and is prevented by pertussis
toxin, suggesting a G protein involvement (311, 365, 411).
PAF-induced activation of PLA2 is also regulated by the
intracellular levels of cAMP (88, 96). The arachidonic acid
metabolites have been shown to mediate several biological activities of PAF. In the heart, PAF-induced coronary
vasoconstriction and reduced contractility are affected
both by cyclooxygenase- and lipoxygenase-derived arachidonic metabolites (334, 335). Furthermore, PAF induces an elevation of cytosolic free calcium in several cell
types including vascular smooth muscle cells (241, 369).
The two main mechanisms involved in PAF-induced increase in cytosolic free calcium are 1) the mobilization of
calcium from the intracellular stores as a result of inositol
trisphosphate generation and 2) the influx of extracellular
calcium through a membrane-associated channel regulated either directly by PAF or indirectly by intracellular
second messenger such as lipoxygenase-derived metabolites of arachidonic acid (100). Calmodulin inhibition
(254) and calcium channels antagonists, such as verapamil (105), were shown to block the influx of 45Ca2⫹ in
rabbit platelets; moreover, verapamil prevents several in
vitro and in vivo biological effects of PAF (12). Recently,
it has been shown that PAF stimulates tyrosine phosphorylation of several proteins in platelets (117), neutrophils
(153), and macrophages (98, 99). Moreover, it was found
that PAF is capable of inducing the stimulation of NF␬B
activation (469) and the transcription of c-fos and c-jun
genes in inflammatory cells (367). Because the PAF receptor contains several tyrosine residues in its intracellular loops and tail, it was suggested that tyrosine phosphorylation may be involved in the downregulation of the
receptor (99). Recently, it has been shown that PAF may
activate a mitogen-activated protein kinase (MAPK) (26,
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375) and may induce the early tyrosine phosphorylation of
focal adhesion kinase (p125FAK) in human endothelial
cells (387). Moreover, in human neutrophils, PAF activates MAPK kinase-3, a known activator of p38 MAPK
(315).
Many antagonists of the PAF receptor have been
described including compounds without any structural
relationship with PAF and structural analogs (for review,
see Refs. 49, 86, 87, 166, 218, 362, 442). The development
of potent and selective PAF receptor antagonists has been
particularly valuable for studies on the pathophysiology
of PAF (136). A number of natural PAF antagonists have
been identified, including BN 52021 and kadsurenone,
isolated from Ginkgo biloba and Piper futokadsura, respectively. More recently, several synthetic PAF receptor
antagonists were also developed. They include 1) phospholipid analogs such as FR 72112, CV 3988, CV 6209, SRI
63441, ONO 6240, and RP 48740; 2) tetrahydrofuran derivatives such as L 652731; and 3) triazolobenzodiazepine
derivatives such as WEB 2086, WEB 2170, BN 50726, and
BN 50739. These chemically different PAF receptor antagonists share the ability to inhibit PAF binding to its
receptor and to antagonize specific PAF-induced responses on target cells.
V. CARDIOVASCULAR RESPONSES
TO PLATELET-ACTIVATING FACTOR
A. Hemodynamic Effect of PAF
The potential regulatory role of PAF on hemodynamics has been extensively studied. This line of research was
initiated by the observation that one of the two antihypertensive lipids isolated from renal medulla and from
renal venous effluent after unclipping one-kidney, oneclip hypertensive rats, the polar renomedullary lipid, has
the same chemical structure of PAF (303, 304, 338). Early
hemodynamic studies emphasized that antihypertensive
polar renal lipid as well as synthetic PAF, in microgram
doses, lowered arterial pressure in guinea pigs (135), rats
(44, 67, 148, 233, 273, 344, 347, 360, 406, 430), and rabbits
(12, 160, 161, 245, 290, 303) in the normal and hypertensive states after intravenous or oral administrations. The
potential role of PAF in the modulation of blood pressure
was inferred from the observation of decreased levels of
PAF (275) and increased activity of plasma acetyl hydrolase (42) in hypertensive rats. Indeed, when administered
intravenously, PAF is hypotensive in all species studied
(134). Despite sensitivity variation among the species,
several characteristics of hemodynamic response to PAF
are common: the extent of hypotension is dose dependent, the onset is very rapid, the maximum effect is
reached within 30 – 60 s, and the recovery time is also
dose dependent. The basal mean arterial pressure (MAP)
is obtained within 5–10 min after intravenous injection. In
animal species such as the rat, where platelets are insensitive to PAF action, no tachyphylaxis was observed (92,
120) In contrast, in the rabbit, where platelets are highly
sensitive to PAF action, tachyphylaxis is present, suggesting that physiological alterations induced by PAF may at
least in part occur via platelet activation and secretion of
other mediators (160). Therefore, the rat model was used
to differentiate direct vascular effects of PAF from those
dependent on the activation of circulating platelets. Table
1 shows hemodynamic alterations induced by PAF infusion in different animal species. Although the mechanisms of PAF-induced hypotension are not completely
understood, some data indicate that the action of PAF on
the heart, peripheral vasculature, and microcirculation
may account, at least in part, for the reduction of systemic
blood pressure. PAF decreases the cardiac output
through several mechanisms: 1) it reduces venous blood
return as the consequence of peripheral vasodilatation or
vasoconstriction and increased microvascular permeability; 2) it produces a right ventricular overload with an
increased right atrial pressure and a reduced filling of left
ventricle as the result of an increase in pulmonary vascular resistance; 3) it may impair cardiac function by a
direct negative inotropic effect and by reduction of coronary blood flow (CBF); and 4) finally, PAF was shown to
affect cardiac electrical activity and the conducting system.
The vascular effects of PAF on blood vessels vary
depending on doses of PAF used, on different districts,
and on animal species. In conscious rats (380), low doses
of PAF increase blood flow and decrease vascular resistances in all vascular districts. High doses of PAF, in
contrast, produced a sustained decrease of cardiac index,
tachycardic response, and transient fall followed by sustained increase of total peripheral resistances (380, 404).
In the mesenteric district, a marked reduction of blood
flow consequent to the increase in mesenteric resistance
was observed (380). These dose-dependent and regional
TABLE
Rat
Guinea pig
Rabbit
Pig
hemodynamic effects of PAF mimic that obtained by infusion of antihypertensive polar renal lipid (129). Moreover, it was found that PAF-induced hypotension is not
mediated through the central nervous system, renin-angiotensin system, muscarinic, ␤-adrenergic, dopaminergic, eicosanoids, calcium influx, thyrotropin releasing hormone, steroids, or histaminergic mechanisms (67, 202,
233, 383). In contrast, it was found that delayed and
persistent but not early hypotension induced by PAF is
inhibited by N␻-nitro-L-arginine, which inhibits the production of nitric oxide from endothelial cells, thus suggesting a role for the “endothelium-derived relaxing factor” (406). In vitro studies demonstrate the involvement of
the nitric oxide pathway in PAF-induced relaxation of rat
thoracic aorta (45, 299). The tachycardic effect of PAF
was inhibited by the ␤-adrenoreceptor blocker propranolol, suggesting a baroreceptor reflex activation consequent to systemic hypotension (326). In rabbit, dog, pig,
and baboon, PAF is a potent activator of platelets and of
leukocytes; therefore, vasoactive substances released
from these cells contribute to the hemodynamic effect of
PAF. The intravenous administration of relatively high
doses of PAF (0.6 – 0.8 ␮g/kg) in rabbits produces bradycardia, reduction of cardiac output, hypotension, decrease of lung compliance, and increase in peripheral
vascular and lung resistances (Fig. 4) (160, 290). The
hemodynamic alterations developed in three sequential
phases: 1) a transient bradycardia (15 s) with reduction in
left ventricular systolic pressure (LVSP), MAP, and cardiac output occurred; 2) a rise in cardiac frequency,
which developed within 30 s, an increase in LVSP, MAP,
total peripheral resistances (TPR), and cardiac output
was observed; and 3) ⬃90 s after PAF infusion, LVSP and
MAP were decreased, whereas TPR and right arterial
systolic pressure persisted elevated. These alterations
were reversed in 30 – 60 min (290). When low doses of
PAF (0.2 ␮g/kg) were used the hemodynamic response
was similar, but the intensity was attenuated (unpublished observations). H1 and H2 histamine receptor antag-
1. Effects of PAF on hemodynamic parameters in different animal species
Species
Dog
1675
PAF AND THE CARDIOVASCULAR SYSTEM
October 2000
Dose
MAP
HR
CO
TPR
MPAP
PVR
Reference
No.
0.3–1
3
0.2
0.38
1.14–1.52
0.038
0.19–0.95
8–36
0.04–0.28
D
D
I/D
D
I/D
D
D
D
D
I
ND
ND
D
I/D
S
ND
D
I
D
ND
ND
ND
D
I
I/D
D
D
D
ND
ND
ND
I
D
D/I
I
I
ND
D
ND
I
ND
ND
I/D
I/D
I
ND
ND
ND
ND
ND
ND
I
I
I
380
92
110
160, 161
290
468
208
35
236
Doses are expressed as nmol platelet-activating factor (PAF)/kg intravenous bolus injection. MAP, mean arterial pressure; HR, heart rate; CO,
cardiac output; TPR, total peripheral resistance; MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistances; I, increase; D,
decrease; S, stable; I/D, increase followed by decrease; D/I, decrease followed by increase; ND, not determined.
1676
MONTRUCCHIO, ALLOATTI, AND CAMUSSI
Volume 80
FIG. 4. Typical hemodynamic changes occurring in a rabbit injected intravenously with
PAF. ECG, electrocardiogram; LVP, left ventricular pressure; dP/dt, derivative pressure/derivative time; FAP, femoral arterial pressure; CVP,
central venous pressure.
onists markedly prevented the development of the second
phase, namely, the rise in cardiac frequency, LVSP, MAP,
and TPR, but did not significantly modify the first and
third phases (290). Moreover, the generation of thromboxane A2 from platelets may contribute to the development of hemodynamic alterations in rabbit. Indomethacin
indeed determined an overall reduction in the extent of
PAF-induced hemodynamic changes (290). These results
suggest that the release of histamine and thromboxane A2
from platelets may in part account for hemodynamic alterations induced by PAF. This was confirmed by the
evidence of entrapment of platelets and leukocytes, particularly in the pulmonary microvasculature (279), and by
experiments of platelet depletion (161). A calcium channel blocker, verapamil, was found to prevent all the hemodynamic and electric alterations induced by PAF (12).
Administration of chronic intravenous PAF induces pulmonary arterial atrophy and hypertension with persistent
increase in pulmonary resistances and reduction in cardiac output (323).
When the effects of PAF infusion were studied in the
anesthetized dogs, a triphasic response was observed (35,
208). In the first phase (15–30 s), hypotension was attributed to a decrease in systemic vascular resistances that
was associated with a rise in cardiac output. The second
phase (30 –90 s) consisted of sustained hypotension
caused by a reduction in cardiac output associated with
an increase in pulmonary and systemic resistances. The
third phase was characterized by a gradual recovery of
MAP, associated with a sevenfold rise in systemic vascular resistances and a persistent low cardiac output. Blockade of leukotriene receptors substantially inhibited the
rise in systemic vascular resistances in the third phase,
suggesting the role of leukotrienes as secondary mediators (208). The vasodilation observed in the first phase
was independent from prostaglandin generation (208,
468). In contrast, the reduction of cardiac output observed in the second phase was shown to depend on
generation of cyclooxygenase metabolites of arachidonic
acid (468). Low doses of PAF caused only the first vasodilatory phase with hypotension (468). Studies performed
in domestic pigs demonstrate an early pulmonary vasoconstriction with a right ventricular failure as the first
determinant of PAF-induced shock. The subsequent decline in cardiac output, underfilling of the left ventricle,
and systemic hypotension were interpreted as the consequence of right-sided events (149, 235, 236).
B. Effect of Local Administration of PAF
on Selected Vascular Districts
In vivo the effects of PAF on selected blood vessels
are masked by the sympathetic vasoconstrictor reflex and
by mediators released from platelets and leukocytes. The
effects of PAF depend on the doses and animal species
(23, 46, 101, 109, 128, 133, 138, 165, 199, 210, 235, 282, 327,
363, 405, 444, 451). In rats, systemic administration of
picomolar amounts of PAF, unable to induce changes of
MAP, reduce vascular resistance and increase blood flow
in the hindquarter, the mesenteric vessels, and the kidney
(211, 380). In contrast, nanomolar concentrations of PAF
injected into abdominal aorta proximal to the superior
mesenteric artery or into the carotid artery induce vaso-
PAF AND THE CARDIOVASCULAR SYSTEM
October 2000
constriction (Table 2) (108, 148, 217). The injection of
PAF into renal artery determines the following dose-dependent alterations: vasodilatation at 1 pmol/kg (165);
initial vasodilatation followed by vasoconstriction at 4 –19
pmol/kg (165), and vasoconstriction at 30 –90 pmol/kg
(23). In dogs, the prominent effect of intrarenal administration of PAF is vasoconstriction for all tested concentrations (24, 363). In contrast, in this animal species, PAF
produces vasodilatation in gastric, mesenteric, and femoral arterial circulation (101). The vasodilator effect on
femoral but not gastric and mesenteric vascular districts
was dependent on prostaglandin synthesis. Moreover, the
block of prostaglandin synthesis enhanced the vasoconstrictor effect of PAF on the renal vascular district (101).
When selected organs are perfused under constant
pressure with low doses of PAF, where blood and autonomic nervous system control were absent, the common
response was vasodilation. In these experimental conditions, PAF induces vasodilation in the kidney (368), but
still produces vasoconstriction in the isolated lung (162,
175) and heart (30, 251, 335).
The question arises whether these experiments reflect only a pharmacological effect or a pathophysiological or a physiological role of PAF. It is hard to answer this
question since it is difficult to measure the actual concentration of PAF in relevant fluids, cells, and tissues because
this mediator is readily metabolized. The concentration of
PAF in cells or tissues depends on the balance between its
synthesis and degradation. The levels of PAF detected in
blood and/or tissues in pathological conditions are in the
range of nanograms and are therefore consistent with the
doses used in experiments of exogenous administration.
Therefore, it is conceivable that PAF may mediate hemo-
2. Effects of PAF on blood flow in selected
vascular districts
TABLE
Species
Rat
Vascular
District
Renal
Cerebral
Mesenteric
Dog
Pig
Renal
Gastric
Mesenteric
Coronary
Femoral
Coronary
Blood
Flow
Reference
No.
0.001 nM
0.004–0.019 nM
0.02–0.1 nM/min
0.03 nM/min
0.2–2 nM/min
7.6 nM
I
I/D
D
D
D
D
0.01–0.38 nM/min
0.04–0.19 nM/min
0.04–0.19 nM/min
0.5–2 nM
0.61–610 nM
0.38–3 nM
0.57 nM/min
0.61–610 nM
0.1–10 nM
1–9 nM/min
D
I
I
I
D
I/D
I
I
I/D
I/D
165
165
23
451
148
108
109
363
101
101
199
405
138
210
405
133
128
Doses
I, increase; D, decrease; S, stable; I/D, increase followed by decrease; ND, not determined.
1677
dynamic changes occurring in pathophysiological conditions such as anaphylaxis and endotoxic shock or acute
and chronic inflammation. Pharmacological agents that
antagonize the binding of PAF to its receptors have been
used to support this contention when it was found that
they attenuate or reverse certain pathological processes.
It is more difficult to evaluate a modulatory role of PAF on
blood pressure in physiological conditions. The fact that
PAF can act as vasodilator at very low concentrations
supports the hypothesis that endogenous PAF may be a
regulator of blood pressure. The levels of PAF in the
blood of normal subjects are in the range of picograms
per milliliter (85, 359). In early studies it has been shown
that PAF was not detectable in anephric hypertensive
patients, suggesting a role of PAF synthesized in renal
medulla in the regulation of blood pressure (85). This
contention was not supported by subsequent studies,
showing that the mean circulating PAF levels in patients
with essential hypertension were not significantly different from those in normotensive subjects (359). However,
it was found that high salt intake significantly increased
the circulating levels of PAF, suggesting the synthesis of
PAF to counteract the hypertensive effect of high dietary
salt intake (359). Recently, it has been shown that there is
an enhanced intracellular PAF-triggered signal transduction in approximately one-third of immortalized lymphoblasts derived from patients with essential hypertension
(157). Moreover, it has been reported that PAF-acetylhydrolase activity in maternal and umbilical venous plasma
was significantly lower in normotensive pregnant women
than in nonpregnant women or in pregnancy-induced hypertension (215). This finding suggests that the inactivation of PAF by acetylhydrolase is decreased during normal pregnancy. Such modulation apparently does not
occur in pregnant women that developed hypertension,
suggesting that the catabolism of PAF plays a relevant
role in the regulation of blood pressure in this contest
(215).
VI. EFFECT OF PLATELET-ACTIVATING
FACTOR ON THE HEART
A. Coronary Circulation: In Vivo Effects
PAF administration into the coronary circulation induced variations in the coronary vascular tone depending
on the doses and the animal species used. In the pig,
intracoronary bolus injection of PAF produced a transient
dose-dependent increase (up to 50%; ED50 ⫽ 0.38 nM) in
CBF followed by a second phase characterized by decrease (up to 92%) in CBF (ED50 ⫽ 0.92 nM) (133). In this
study it was shown that at low doses of PAF (0.03– 0.3
nM), both the increment and the decrement of CBF was
present in the absence of significant changes in systemic
1678
MONTRUCCHIO, ALLOATTI, AND CAMUSSI
blood pressure. In contrast, the reduction in CBF caused
by high doses of PAF was accompanied by significant
decrease in systemic blood pressure and by electrocardiogram signs of ischemia such as S-T segment elevation
or depression when flow decreases by more than 75% of
control values. Similar results were reported after continuous intracoronary infusion of PAF in the pig (128, 134).
Pharmacological studies demonstrated that the early increase in CBF is independent from the generation of
cyclo- and lipoxygenase-derived metabolites, while the
subsequent vasoconstriction is primarily due to the production of thromboxane A2 (133). PAF induces coronary
vasoconstriction and S-T depression also in rabbits (290).
Conflicting effects were observed in dogs (199, 282, 405).
In one study it was shown that intracoronary injection of
PAF reduced CBF concomitantly with a marked and rapid
reduction in systemic arterial pressure and a negative
inotropic response, effects that could have obscured the
direct action of PAF on coronary artery (405). In other
studies, similar doses of PAF are reported to produce a
platelet-dependent coronary vasodilation (199) or a biphasic vasodilator/vasoconstrictor effect (282). In subsequent studies, it was found that PAF is vasodilator when
the endothelium of coronary arteries is intact, whereas it
induces vasoconstriction when the endothelium is injured
as it may occur after ischemia (210). In vivo studies
provided evidence that PAF induced a significant attenuation of endothelium-dependent dilation to intracoronary
infusion of acetylcholine and serotonin, further suggesting an endothelial effect of PAF (111).
B. In Vitro Effects on Isolated Perfused Heart
In the isolated guinea pig heart perfused at constant
pressure, PAF produced a dose-dependent increase in
coronary vascular resistances (30, 149, 208, 251, 335, 398).
This vasoconstrictor effect of PAF was completely
blocked by verapamil, a calcium antagonist (12). Pharmacological inhibition of cyclooxygenase and blockade of
leukotrienes receptors were reported ineffective by Levi
et al. (251) and Stahl et al. (398), while PAF receptor
antagonists reduce the coronary vasoactive effect of PAF
(335, 410, 447, 448). Similar coronary vasoconstriction
was obtained with high doses of PAF in isolated perfused
rat heart (334, 397). However, when low doses were used,
vasodilation alone or vasodilation followed by vasoconstriction was observed (187, 188). Pharmacological studies on the action of PAF on isolated rat heart suggest that
both prostaglandins and leukotrienes are involved in the
vasoconstrictor effect of PAF. However, it has been
shown that lipoxygenase products are mainly responsible
for the vasodilator and vasoconstrictor effects of PAF on
coronary vasculature, whereas cyclooxygenase products
play only a partial role (147, 265, 334, 397). In the isolated
Volume 80
perfused rabbit heart, the coronary vasculature was apparently insensitive to PAF (208, 283, 291). However,
when isolated rabbit heart was perfused with blood, PAF
markedly reduced coronary flow (208). The isolated rabbit heart was used as a model to study in vitro interaction
between platelets, leukocytes, and endothelial cells in the
coronary circulation. In the rabbit heart perfused with
platelets, the infusion of PAF induced a dose-dependent
decrease of coronary flow, which was prevented by pretreatment of the heart with H1 and H2 histamine receptor
antagonists and a leukotriene receptor antagonist (291). A
similar protective effect was obtained after treatment of
platelets with prostacyclin, which inhibits the activation
of platelets by PAF (8). Perfusion of rabbit heart with
PMN followed by PAF stimulation did not alter coronary
tone (10). However, PMN may influence the effect of PAF
on coronary vessels as a result of cooperation with platelets. The reduction of coronary flow induced by PAF in
rabbit heart perfused with platelets and PMN was completely blocked by a leukotriene receptor antagonist, suggesting that leukotrienes released by PMN as a consequence of a PAF-induced cooperation with platelets are
the main mediators of coronary constriction (10). This
evidence is also supported by experiments of perfusion of
rabbit heart with N-formyl-L-methionyl-L-leucyl-L-phenylalanine-activated PMN (417). In this experimental condition, PAF antagonist inhibited the neutrophil-dependent
increase in coronary resistances (417). Similar results
were obtained in studies on the PMN-induced contraction
of the isolated rings of cat coronary artery (307). In humans, in basal conditions isolated coronary artery rings
did not react to PAF challenge. However, Soloviev and
Brachet (388) have shown that isolated human coronary
artery strips after hypoxia undergo to a PAF-dependent
biphasic contraction: an initial short phase of contraction,
followed by a longer tonic shortening inhibited by treatment with a PAF receptor antagonist.
C. Myocardial Function
The alterations in cardiac function, including the reduction in cardiac output observed in vivo after infusion
of PAF, can result either from a direct action on the heart
or from indirect effects such as systemic changes and
variations in pre- and afterload pressures. Furthermore,
alterations in cardiac performance may depend on the
effect of PAF on the coronary circulation, on the conduction system, and on the contractile properties of myocardium (150).
A direct effect of PAF on cardiac contractility was
suggested by experiments of intracoronary infusion of
low doses of PAF in pig, that induced a marked reduction
in cardiac output as well as in regional shortening fraction
in the absence of significant effects on systemic blood
October 2000
PAF AND THE CARDIOVASCULAR SYSTEM
pressure (126, 128, 133, 134). In in vitro experiments on
the isolated coronary perfused heart, the effect of PAF is
quite different, depending on the animal species studied.
In guinea pig isolated heart perfused at constant pressure,
infusion of PAF reduces the force of contraction and the
coronary flow in a dose-dependent manner. Moreover,
PAF markedly alters the electrical activity of the heart
(351); the severity and duration of these alterations are
related to PAF dosage. PAF induces conduction arrhythmias, ranging from second degree atrioventricular conduction block to complete atrioventricular dissociation
and ventricular extrasystoles, disappearance of the T
wave, and depression of the S-T segment, a sign of myocardial ischemia (12, 30, 253, 357, 398, 410). The studies of
ventricular action potentials by means of intracellular
electrodes have shown that after the infusion of PAF the
action potential duration progressively shortens, and the
resting membrane potential, the overshoot, and the maximum rate of depolarization, which are initially unchanged, progressively reduce 10 min after the challenge
(12). The response to PAF is prompt and long lasting; the
maximal effect is reached within 2 min after the challenge. At 10 nM, PAF causes irreversible conduction arrhythmias so that the normal sinus rhythm and cardiac
contractility do not return even after a prolonged perfusion with physiological solution without PAF. These effects seem to be independent from the release of acetylcholine from the nerve endings, since pretreatment with
atropine does not affect the action of PAF (30). Moreover,
the effects of PAF are independent from the generation of
secondary mediators derived from the arachidonate metabolism, since neither the cyclooxygenase inhibitor indomethacin, nor the thromboxane synthetase inhibitors,
nor the leukotriene receptor antagonists significantly
modify the response to PAF (251, 253). In these experiments, peptide leukotrienes or thromboxane B2 were not
detected by radioimmunoassay in the coronary effluent
(398). However, pretreatment of the heart with the calcium antagonist verapamil significantly reduces the entity
of PAF-induced coronary spasm and completely abrogates both the electrical and mechanical alterations (12).
The entity of cardiac alterations induced by PAF is related
to the molecular structure for different species of PAF. In
particular, the most potent species of PAF in inducing
coronary constriction in the guinea pig heart was 18:1
PAF, whereas 16:0 and 18:0 had minor effects. The order
of potency in reducing contractile force was 16:0 ⬎
18:1 ⬎ 18:0. Therefore, the presence of a single double
bond in the alkyl chain at the sn-1 position markedly
alters the cardiac activity of alkyl-PAF (252, 280). In contrast to PAF, its deacetylated derivative lyso-PAF causes
no significant variation in contractile force, coronary
flow, and cardiac rhythm (251). The effects of PAF are
also present in the isolated heart perfused at constant
flow; in this case, a dose-dependent increase in coronary
1679
resistance is observed (251). Because a reduction of cardiac inotropism and alteration of cardiac rhythm induced
by an intracoronary infusion of PAF are also present
when the guinea pig isolated heart is perfused at constant
pressure, it is unlikely that the effects of PAF depend on
an ischemic state consequent to a reduction of coronary
flow.
The effects induced by PAF in the isolated rat heart
are similar to that observed in guinea pig heart (e.g.,
reduction in coronary flow and developed pressure, increase in diastolic pressure and conduction arrhythmias)
(188, 189, 334, 339, 340). In this animal, however, it has
been shown that the PAF-induced coronary vasoconstriction is mediated by the peptide leukotrienes (leukotriene
C4 and leukotriene D4) (188, 189, 334). This finding indicates that in the rat heart PAF may have a small direct
negative effect, whereas the reduction of coronary flow
consequent to production and release of endogenous leukotrienes appears to induce a major depression of cardiac
contractile force. Arachidonic acid metabolites released
by PAF may stimulate the release of atrial natriuretic
factor in rat heart (348, 349). Interestingly, comparison of
the effect of PAF in adult and senescent rats shows that
all the electrical and mechanical alterations induced by
PAF are more marked in the senescent hearts (1). Isolated
rabbit heart is responsive to PAF only if blood (208),
platelets, and platelets plus leukocytes are present in the
coronary vessels (283, 291). In these conditions, PAF
induces mechanical and electrical alterations similar to
those observed in the isolated guinea pig heart.
D. Atrium and Papillary Muscle
The isolated perfused heart preparation does not
differentiate the direct negative inotropic effect of PAF
from that consequent to changes in coronary flow and O2
delivery to the heart. Therefore, the isolated atrium and
papillary muscles were used to address the direct effect of
PAF on cardiac muscle. In isolated rat atrium, PAF does
not elicit significant effects on chronotropy and inotropy
at concentration up to 3 ⫻ 10⫺5 M (89). At the concentration 1 ⫻ 10⫺4 M, PAF induces positive chronotropic
and inotropic effects on isolated spontaneously beating
right and electrically driven left atria. Both effects were
blocked by propranolol, whereas reserpine pretreatment
antagonized only the chronotropic response. Studies on
isolated guinea pig atrium and papillary muscle (71, 118,
251, 407) showed a direct negative inotropic effect of
PAF. Lyso-PAF caused only minimal effect (⬃5%) on
these preparations. We studied the effect of PAF on the
electrical activity of guinea pig papillary muscle by means
of intracellular electrodes (71). PAF at 2 ⫻ 10⫺10 M induces a biphasic effect with an increase of 20% of contractile force within 2–3 min after the challenge, followed
1680
MONTRUCCHIO, ALLOATTI, AND CAMUSSI
by a progressive decrease of developed tension, which
was reduced by 50 – 60% with respect to control values.
The positive inotropic effect was preceded by a slight
augmentation of action potential duration (APD); subsequently, APD decreased concomitantly with the negative
inotropic effect. Pretreatment with propranolol prevented
the positive inotropic effect and increase of APD. Similar
biphasic dose-dependent effect of PAF was observed in
guinea pig papillary muscle by Tamargo et al. (407). Moreover, these authors showed that at high concentrations of
PAF (10⫺9 to 10⫺7 M), reduction of APD was accompanied by increase of action potential amplitude, maximum
rate of depolarization (MRD), and resting membrane potential (Er) of the action potential. Short runs of spontaneous discharges of ventricular muscle fibers accompanied the electrophysiological effects of PAF at all
concentrations tested. A similar biphasic dose-dependent
effect was described by Gollasch et al. (152), Kecskemeti
(206), and Kecskemeti and Braquet (207) in guinea pig
auricles: 10⫺10 M PAF induces transient positive inotropic
effect followed by a negative one; 10⫺7 M PAF induces
negative inotropism accompanied by decrease in amplitude, duration, and MRD of the action potential without
changes in Er. The effect of PAF was reversed after washout of PAF. The study on the slow action potential was
performed in these preparations to obtain insight into the
mechanism of PAF-induced negative inotropism and decrease of APD. However, the results of these studies are
partially conflicting. For instance, we reported that PAF
induces a transient positive inotropic effect and enhancement of the slow action potential, followed by a profound
depression of both the electrical and mechanical activities, suggesting a biphasic effect of PAF, i.e., an initial
stimulation followed by depression of slow calcium channels (71). In contrast, Tamargo et al. (407) and Robertson
et al. (353) found that PAF induces only a dose-dependent
increase in amplitude and MRD of slow action potentials.
These discrepancies are probably due to the different
methods used. In our study, slow action potentials were
obtained by elevating both K⫹ and Ca2⫹ extracellular
concentrations to 22 and 6 mM, respectively, to inactivate
the fast Na⫹ current and increase the driving force for
Ca2⫹, while in the case of Tamargo et al. (407) and Robertson et al. (353) papillary muscles were bathed in
high-K⫹ solution with the addition of isoproterenol or
histamine to obtain slow action potentials. These drugs
are known to stimulate adenylate cyclase via specific
receptors, to increase the intracellular levels of cAMP,
and to activate protein kinase A, leading to phophorylation not only of the Ca2⫹ channel protein but also of a
large number of other substrates within the cell. It has
been reported that after pretreatment of papillary muscle
with isoproterenol, which per se has a positive inotropic
effect, PAF further enhances action potential amplitude
Volume 80
and duration, as well as the force of contraction, while the
second phase (depression of action potential and contractility) is absent. These results are consistent with that
observed in the isolated rat heart by Bensard et al. (28),
that PAF depresses basal myocardial function and enhances the functional response to ␤-adrenergic stimulation. Finally, the direct demonstration of the involvement
of calcium current comes from voltage-clamp experiments on frog and guinea pig atrial fibers, in which Gollasch et al. (152) showed that the negative inotropic effect
of PAF is accompanied by a significant reduction of this
current. The mechanical and electrical changes induced
by PAF were studied in human cardiac preparations such
as the isolated papillary muscle (11) and atrial tissue
(352). Challenge of human papillary muscles excised from
the left ventricle by open heart surgery with various doses
of PAF (1 ⫻ 10⫺10 to 1 ⫻ 10⫺6 M) induced a biphasic
dose-dependent effect, characterized by a transient positive effect on inotropism and APD, followed by a marked
prolonged negative effect on force of contraction and
APD. No changes in Er, overshoot, and MRD of the action
potential were detected after PAF challenge (11). Robertson et al. (352) reported a similar dose-dependent negative inotropic effect of PAF in human atrial muscle. However, lyso-PAF has no effect on contractile activity in both
cardiac preparations, even at concentration up to 100-fold
greater than those of PAF. In human papillary muscle,
propranolol blocked the transient inotropic effect of PAF,
suggesting a stimulation of ␤-receptors by endogenous
catecholamines; pretreatment with indomethacin did not
modify the initial positive effect, but markedly reduced
the negative effect of PAF (11). In contrast, in human
atrial tissue, the effect of PAF was blocked by antagonists
of PAF receptor, but not modified by atropine, indomethacin, and the leukotriene receptor antagonist FPL 55712,
suggesting a direct effect of this mediator (352). Moreover, it was shown that the decrease of contractile force
caused by PAF in guinea pig papillary muscle may depend
on the reduction of intracellular sodium activity, which
may affect sodium/calcium exchange, finally causing reduction of intracellular calcium and contractility (353).
E. Effects on Cardiomyocytes
The direct effects of PAF on cardiac inotropism and
chronotropism have been studied in isolated adult or
cultured neonatal cardiomyocytes (112, 272). In this experimental condition, PAF was shown to decrease myocardial twitch tension and velocity of contraction and
relaxation as well as to increase spontaneous beating
frequency (272). Recently, it has been shown that PAFinduced negative inotropic effect correlated with a decrease in systolic intracellular calcium concentration
October 2000
PAF AND THE CARDIOVASCULAR SYSTEM
(331). Parallel biochemical studies demonstrated that
PAF stimulates phosphoinositide pathway, leading to accumulation of [3H]inositol phosphate and activation of
PKC in cardiomyocytes (102). Because it has been shown
that blockade of PAF receptors prevented both mechanical and biochemical changes induced by PAF, the presence of PAF receptors on cardiomyocytes may be suggested. The PAF receptor gene in human cardiomyocytes
(403) has been recently cloned and characterized. Moreover, the patch-clamp technique has been applied to the
study of electrophysiological effects of PAF on isolated
guinea pig ventricular and atrial cells. Single-channel
studies on cell-attached patches have shown that PAF
affects inwardly rectifying background potassium channels (IK1) (450). PAF initially induces a flickering of the
channel, followed by a gradual prolonged depression of
the channel activity. Because these potassium channels
have a prominent role in determining the resting potential
and excitability of the cardiac cells, it has been suggested
that the effect of PAF on IK1 may play a major role in the
electrophysiological action of PAF in the heart. Moreover,
PAF was shown to stimulate cardiac muscarinic potassium channels in isolated guinea pig atrial cells. The effect
of PAF was prevented by specific PAF receptor antagonists, lipoxygenase and PLA2 inhibitors, but not by cyclooxygenase antagonists. The opening of the channel was
shown to be dependent on the activation of a G protein
(309). Similar results were obtained using isolated bullfrog atrial myocytes (346). In contrast, in human and
chick ventricular myocytes, PAF was found to stimulate
T- and L-type calcium currents in a dose-dependent manner, whereas no effect on fast sodium current or delayed
outward potassium current was observed. The effect of
PAF on calcium currents was receptor dependent, because it was inhibited by PAF receptor blockade with
WEB 2170 (41). The different response to PAF of cardiomyocytes derived from atrium or ventriculum suggests a
functional differentiation of these cells.
Moreover, it as been shown that PAF induces secretion of atrial natriuretic peptide (103, 348, 349) and eicosanoids (27) in spontaneously beating neonatal rat cardiomyocytes.
VII. MICROVASCULAR EFFECT OF
PLATELET-ACTIVATING FACTOR IN VIVO
The potent vasoactive and leukotactic properties of
PAF were initially studied in the rat cremaster muscle and
skin after infusion of colloidal carbon and local injection
of PAF (191). PAF was shown to be 1,000 –10,000 times
more potent than histamine on molar basis in inducing
vascular permeability (191). Ultrastructural studies demonstrated subendothelial carbon accumulation in the
1681
postcapillary venules. A concomitant leukocyte margination was observed. However, the vasoactive properties
of PAF in the rat appeared to be neutrophil and platelet
independent. A direct stimulation of venular and endothelial cells was suggested. The effect of PAF on microcirculation has been studied also on the hamster cheek
pouch (89, 119). Vasoconstriction was the predominant
vasomotor response to PAF. This biological effect was
dependent on the dose of PAF and the size of the vessel
and was mediated by PAF receptor interaction and production of thromboxane A2. In addition, PAF increases
vascular permeability both by a direct mechanism and
platelet- and leukocyte-mediated mechanisms (119). It
was found that PKC activation is an in vivo biochemical
pathway in the signal transduction of PAF-stimulated microvascular cellular responses, leading to increases in the
transport of the macromolecules. Indeed, PKC inhibitors
significantly blocked the increase in intravascular permeability (214). In contrast, they did not interfere with the
PAF-induced arteriolar constriction (214). Studies on intestinal microvasculature have shown that PAF promotes
the filtration of fluid and protein across intestinal capillaries in cats (226). These microvascular effects of PAF
are mediated in part by adherent leukocytes (226, 227). In
the guinea pig, PAF causes a dose-dependent increase in
airway vascular permeability, as measured by extravasation of Evans blue dye, at concentrations as low as 1 ng/kg
(168). The site of leakage, as for other mediators, is in the
postcapillary venules. This effect of PAF is receptor mediated and platelet independent, as it is inhibited by receptor antagonists, but not by platelet depletion. PAF also
affects mean renal vascular resistance (23) and glomerular permeability (82, 364) by a dual mechanism: 1) it
enhances size permeability of glomerular basal membrane by a direct action on the glomerular capillary wall
(330), and 2) it modifies perme-selectivity owing to a loss
of fixed negative charges of the glomerular capillary wall
due to the release of cationic proteins from PAF-activated
platelets and neutrophils (82). Intradermal injection of
PAF into the skin of human volunteers has been reported
to produce an immediate vasoconstriction followed by a
vasodilatation and an increase in vascular permeability
(19). The increase in plasma protein extravasation elicited
by PAF was enhanced by concomitant intradermal injections of prostaglandin E2 or prostaglandin E1 and inhibited by a ␤-adrenoceptor agonist (isoprenaline) or an
␣-adrenoceptor agonist (phenylephrine) (300). The effect
of PAF on vascular permeability was independent from
the stimulation of H1 histamine receptor (191). Recently,
it has been shown that the synthesis of PAF mediates the
increase in vascular permeability induced by vascular
endothelial growth factor (VEGF) in certain organs, such
as stomach, duodenum, and pancreas (381), but not in
skin (308).
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MONTRUCCHIO, ALLOATTI, AND CAMUSSI
Volume 80
VIII. EFFECTS OF PLATELET-ACTIVATING
FACTOR ON ENDOTHELIAL CELLS
B. Endothelium-Leukocyte and
-Platelet Interaction
Endothelium modulates the microenvironement homeostasis by affecting the traffic of macromolecules and
cells from the bloodstream to the tissue. The molecules
involved in the control of such traffic are soluble mediators, surface receptors that translate external signals and
adhesion molecules. In this setting, PAF acts as an autocrine (176) and paracrine mediator that may modulate
endothelial functions. Several stimuli are capable of inducing the synthesis of PAF from endothelium including
thrombin, vasoactive mediators, and proinflammatory cytokines, suggesting that PAF may transduce or amplify
the signals delivered by these mediators. The two main
endothelial cell functions regulated by the synthesis of
PAF are the endothelial cell barrier function and the
adhesion of leukocytes to the endothelial layer, which
precedes their transmigration.
Three subsequent steps are thought to be involved in
neutrophil migration from bloodstream to inflamed tissues (66). The first step requires a transient interaction of
leukocytes with the endothelial cells mediated by surface
molecule known as selectins. This interaction induces the
rolling of leukocytes along the vessel wall, but it is not
strong enough to completely stop them. The second step
involves the activation of the leukocytes brought, by selectins, into contact with endothelium. This activation
leads to a stable adhesion dependent on the interaction of
integrins expressed on the surface of leukocytes with the
endothelial counter receptors belonging to the superfamily immunoglobulins. In the third step, chemoattractants
stimulate the transmigration of leukocytes across the vessel wall (390). PAF is considered a mediator of leukocyteendothelium interaction, which may participate in the cell
activation phase (479, 480). Prescott et al. (336) correlated the adhesion of neutrophils to thrombin-activated
endothelium with the PAF synthesized and expressed on
the surface of endothelial cells. By using specific PAF
receptor antagonists, they demonstrated that PAF produced by stimulated endothelial cells was a crucial determinant in neutrophil adhesion to endothelium. PAF produced after thrombin stimulation is coexpressed with
P-selectin on the endothelial cell surface. It has been
suggested that P-selectin triggers and PAF activates neutrophils by interacting with its specific receptor (259,
376). This leads to an influx of calcium ions in neutrophils
associated with the upfunctional regulation of CD11/
CD18 integrin complex and the cell polarization (259).
Moreover, PAF was shown to play a different role when
endothelial cells are stimulated by cytokines such as IL-1
(61, 228, 229) or TNF-␣ (64, 228). Cytokines promoted the
neosynthesis and coexpression on the endothelial cell
surface of a selectin (E-selectin) (390) and of PAF. The
latter promoted a calcium influx in adhering neutrophils
(228, 229) that enhanced their response to the IL-8 produced by endothelial cells (228). PAF was not essential in
the delayed cytokine-induced PMN adhesion (228, 229)
but was involved in neutrophil emigration, because PAF
receptor antagonists were shown to block the neutrophil
migration across monolayers of cytokine-pretreated endothelial cells (228). The difference in the role of PAF
exposed on endothelial cell surface after thrombin or
cytokines treatment may depend either on differences on
molecules coexpressed on the endothelial cell surface or
on the amount of PAF exposed. Finally, exogenously
added PAF increases the endothelial cell proadhesive
properties for leukocytes (336, 376, 476, 477) and promotes their transendothelial migration (88). In this experimental condition, PAF stimulates the endothelial cell
receptor, promoting the expression of P-selectin and a
A. Effect of PAF on Endothelial Cell Permeability
The endothelium was shown to express PAF-binding
sites (223) and to be a target for PAF (62). Therefore, PAF
produced by endothelial or inflammatory cells may stimulate endothelial cell functions. In vitro PAF enhances the
permeability of cultured human endothelial cell monolayer and induces changes of the cell cytoskeleton leading
to cell retraction and formation of intercellular gaps (62).
Specific PAF receptor antagonists (62) inhibit these effects. Shape change of bovine pulmonary endothelial cells
was also obtained in the presence of PAF (57, 155). Moreover, PAF induces the production from endothelial cells
of several vasoactive mediators. PAF stimulation of cultured human endothelial cells (117a) induces a dose-dependent synthesis of prostacyclin and thromboxane A2, or
release of plasminogen activator (124). In addition, the
changes in shape of endothelial cells were associated with
activation of calcium-dependent K⫹ channels and hyperpolarization of cell membrane. PAF induced an increase
in cytosolic free calcium through the production of inositol trisphosphate (41, 54, 58, 155), and possibly the opening of receptor-operated calcium channels may serve as a
signal for increasing macromolecular transport and activation of PLA2. The stimulation of PLA2 may lead to the
synthesis and release of leukotrienes and thromboxane
A2, which are involved in PAF-induced permeability
changes and arteriolar constriction, respectively. Recent
studies on the basic mechanism by which leukocyte-endothelial cell adhesion mediates PAF-induced increases
in capillary permeability demonstrate a correlation between the extent of arteriolar pairing to venules and the
PAF-induced increase in capillary fluid filtration rate
(170).
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PAF AND THE CARDIOVASCULAR SYSTEM
rapid and selective loss of sulfated proteoglycans, thus
reducing the charged repealing forces between cells
(376). Indeed, it has been shown that PAF plays a critical
role in monocytes as well as neutrophil migration across
monolayers of cytokine-prestimulated endothelial cells
(228). Recently, it has been shown that integrins are upregulated by PAF and that the ␤1-integrins are critically
involved in PAF-induced leukocyte locomotion in extravascular tissue (454). Moreover, platelet/endothelial
cell adhesion molecule-1 has been involved in PAF-induced cell activation, suggesting that platelet/endothelial
cell adhesion molecule-1 may serve as a costimulatory
agonist receptor capable of modulating integrin function
in human platelets during adhesion and aggregation (443).
These mechanisms of leukocyte recruitment were
shown to play a critical role in the ischemia-reperfusion
injury (Fig. 5) (261). Indeed, it was found that cultured
human endothelial cells exposed to sublethal anoxia followed by reoxygenation induced PAF synthesis (84) and a
leukocyte adhesion and transmigration that was inhibited
by PAF receptor antagonists (20, 194, 201, 284, 345, 471).
It was found that cultured human endothelial cells and
neonatal rat heart myocytes synthesize PAF after prolonged hypoxia (56). Moreover, several studies demonstrated that monoclonal antibodies against adhesion molecules as well as antagonists of selectins or of PAF
significantly prevented the recruitment of leukocytes in
ischemic heart and reduced the necrotic area (261, 287,
307).
The role of PAF as mediator of direct interaction
between platelets and endothelium is controversial. In
vitro studies have shown that exogenously added PAF did
not promote platelet adhesion to an endothelial monolayer. However, it has been recently shown that PAF, but
not leukotriene B4, induces the adhesion of platelets to
the endothelium in the presence of activated PMN (180 –
182). The inhibitory effect of PAF receptor antagonists
suggests that PAF mediate a PMN-platelet interaction.
The generation of oxygen radicals from activated PMN
was shown to stimulate the subsequent adhesion of platelets to the endothelium (182).
IX. INVOLVEMENT OF PLATELET-ACTIVATING
FACTOR IN CARDIOVASCULAR
PATHOPHYSIOLOGICAL PROCESSES
A. Role of PAF in Cardiac Anaphylaxis
and Shock Syndromes
Cardiac anaphylaxis defines the involvement of the
heart as a target organ of immediate hypersensitivity
reaction. The in vitro studies on isolated guinea pig
heart passively sensitized to dinitrophenol demonstrated a coronary vasoconstriction, impaired myocardial contractility, and arrhythmias following the antigen
challenge (251). A hallmark of cardiac anaphylaxis is
the release of mediators such as histamine, thromboxane A2, prostacyclin, and leukotrienes (5, 6, 251, 334).
During anaphylaxis PAF is released in the coronary
effluent of the isolated guinea pig heart (251). Moreover, when administered to isolated perfused heart,
PAF reproduces the mechanical and electrical changes
typically encountered during allergic reactions (e.g.,
rightward shifts in the QRS axis, ischemic S-T segment
changes, and brady- and tachyarrhythmias) (30, 251,
334, 335). In vivo, an intravascular release of PAF occurs during experimentally induced anaphylaxis in rab-
FIG. 5. Role of PAF in leukocyte recruitment and transmigration in injured
myocardium. P-selectin contained in the
bodies of Weibel-Palade (WP) is coexpressed with PAF on the surface of endothelium activated by hypoxia/reoxygenation. P-selectin by recognizing its
counterreceptor sialyl Lewis X (sLex) allows a transient adhesion of leukocytes
leading to interaction of leukocyte PAF
receptor (PAF-Rc) with PAF expressed
on the endothelial cell surface. PAF stimulates an upfunctional regulation of
CD11/CD18 integrin complex, making it
competent to bind specific endothelial ligands such as intercellular adhesion molecule-1 (ICAM-1), leading to a firm adhesion. Moreover, PAF acts in concert with
interleukin-8 (IL-8) in promoting the
transmigration of leukocytes in the extravascular space. LTB4, leukotriene B4;
PMN, polymorphonuclear neutrophils;
EC, endothelial cells.
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MONTRUCCHIO, ALLOATTI, AND CAMUSSI
bits and implies a relationship between PAF and other
mediators (110, 132, 160, 161, 332). It has been shown
that the action of PAF on isolated rat heart was dependent on the release of leukotrienes and of cyclooxygenase products with vasoconstrictor action (334). A partial protective effect of PAF antagonists in anaphylactic
reactions further supports the role of PAF. BN 52021
and WEB 2086 were shown to inhibit cardiac anaphylactic responses such as coronary constriction and decreased contractility of passively sensitized guinea pig
hearts (219, 264). Moreover, the PAF receptor antagonists were shown to reduce significantly the sustained
vasoconstriction induced by challenge with ovalbumin
of presensitized animals (220). Even though indomethacin suppresses the production of 6-keto-prostaglandin
F1␣ and thromboxane B2, it did not affect vasoconstriction during anaphylaxis (401). These observations suggest that PAF-induced coronary constriction depends
on leukotriene production rather than thromboxane A2.
In addition, PAF has been involved in the pathogenesis
of immune complex-induced and septic shock. PAF was
implicated in the hemoconcentration and the systemic
enhancement of vascular permeability induced by infusion of immune complexes or IgG aggregates (167, 361).
In this experimental condition, PAF also mediates leukopenia and thrombocytopenia induced by the immune
complexes (81). Moreover, PAF has been considered a
mediator of septic shock (75, 78, 137) on the basis of
the following evidence: 1) when administered in experimental animals PAF reproduces several aspects of the
lipopolysaccharides (LPS)- or TNF-␣-induced shock
(70, 134, 306, 344, 412). 2) PAF is synthesized during
septic shock (120) by several cell types including monocytes, PMN, Kupffer cells, splenic cells, and endothelial
cells stimulated either by LPS (74, 159, 198, 238), bacterial exotoxins (55, 225), porins (432), or TNF-␣ (64,
73, 440). Recently, we demonstrated that LPS-binding
protein and CD14 (463) modulate the synthesis of PAF
induced by LPS (74). 3) Transgenic mice overexpressing PAF receptor show an increased mortality when
exposed to bacterial endotoxin (197). 4) PAF receptor
antagonists inhibit or reverse endotoxin/TNF-␣-induced hypotension and reduce mortality (4, 86, 93, 120,
140, 166, 205, 324, 325, 343, 370, 406, 412, 422, 462, 465,
467, 473). It has been shown that a variety of chemically
unrelated PAF antagonists inhibit and/or reverse also
the endotoxin-induced leukopenia, thrombocytopenia,
and hemoconcentration (4, 107, 234, 422). Moreover,
PAF receptor blockade has been shown to improve
cardiovascular function in nonhypotensive sepsis (2,
125). Further support for the role of PAF was provided
by the observation that a PAF receptor antagonist attenuates the induction of the cytokine network in experimental endotoxemia in pigs (462) and chimpanzees
(230). Therefore, it has been suggested that PAF is the
Volume 80
most proximal mediator in the cytokine cascade triggered by endotoxin or sepsis (230). There is evidence
suggesting that PAF contributes to the pathogenesis of
cardiac, lung, and renal complications of septic shock
(328). Several negative inotropic substances such as
TNF-␣ and IL-1 are present in the circulation (231).
Because PAF was shown to mediate several biological
effects of TNF-␣ (68), it is therefore a potential candidate for mediation of cardiac function depression in
septic shock (11, 13, 30, 178, 205). In the guinea pig
papillary muscle, cardiac alterations induced by TNF-␣
are mediated by PAF and nitric oxide, the production of
which is downstream to the synthesis of PAF (13).
Recently, it has been shown that PAF mediates the
action of LPS on coronary microcirculation in isolated
perfused rat heart (83). Moreover, PAF antagonists
were shown to prevent systemic and pulmonary hemodynamic changes as well as acute lung and renal vascular injury in endotoxin-treated rats (92, 328, 420,
451). In the kidney, the synthesis of PAF from glomerular mesangial cells and endothelial cells may be triggered either directly by LPS or other bacterial products
such as porins or by LPS-induced cytokines such as
TNF-␣ and IL-1 (36, 72, 432). PAF extracted from kidney is increased in endotoxic shock, and PAF receptor
antagonists not only prevent but also revert the normotensive LPS-induced hemodynamic insufficiency in rats
(420, 451). In humans, thrombocytopenia and reduction
of PAF free receptors were observed in septic shock,
and the involvement of platelets was correlated with
development of adult respiratory distress syndrome
(ARDS) (258, 274, 389). Moreover, PAF has been detected also in bronchoalveolar lavage of patients with
ARDS (274). A preliminary trial in which a PAF receptor antagonist has been used in the treatment of patients with septic shock has been recently published.
This study suggests that mortality is reduced in gramnegative but not in gram-positive septic shock (116).
Furthermore, studies on anesthetized rats support
the role of PAF in mediating traumatic shock. An increased content of PAF in the peritoneal fluid of traumatized rats and a partial protection from shock of several
PAF receptor antagonists has been reported (393, 395,
413). On the basis of experiments with PAF receptor
antagonists, PAF has been also implicated in hemorragic
shock (3, 271, 394) and in postischemic shock reaction
(358), although no direct evidence is available on an
enhanced synthesis of this mediator.
B. Role of PAF in Ischemia-Reperfusion Injury
of the Heart
The role of PAF in ischemia and reperfusion injury of
the heart is supported by experiments aimed at evaluating
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PAF AND THE CARDIOVASCULAR SYSTEM
the synthesis of PAF and the protective effect of PAF
receptor antagonists in these physiopathological conditions (47). Myocardial synthesis of PAF occurs in baboons
following myocardial infarction (17), and an intravascular
release of this mediator was detected in blood of patients
with coronary artery disease undergoing atrial pacing to
evaluate the severity of ischemia (294). Moreover, PAF
was detected in the coronary sinus after occlusion and
reperfusion injury in sheep (212). Indirect evidence for
PAF biosynthesis during myocardial ischemia was obtained measuring the lyso-PAF, a metabolite of PAF, in
canine myocardium subjected to permanent ligation of
the left anterior descending coronary branch (247). Experiments on isolated perfused hearts demonstrated the
cardiac origin of PAF released in significant amounts
during ischemic reperfusion injury. In rabbits, PAF was
detected in the coronary effluent during the initial reperfusion of ischemic heart (34, 204, 291). The release of PAF
was concomitant with that of 6-keto-prostaglandin F1␣
(34). The precise cellular source of PAF was not identified
in this model; however, likely candidates are endothelial
cells (69, 276, 278, 336, 478) and cardiomyocytes (56).
Indeed, it has been reported that cultured endothelial
cells (20, 471) as well as cultured neonatal rat heart
myocytes synthesize PAF after prolonged hypoxia (56). In
the isolated rabbit heart, the effects of PAF were platelet
dependent (291). When reperfusion was performed in the
presence of autologous platelets, there was a significant
worsening of left ventricular function and an increased
rate of ventricular arrhythmias, which were prevented by
a PAF receptor antagonist (90). The effect of platelets was
due to the release of histamine, thromboxane A2, and
leukotrienes (291). It was shown that a PAF-dependent
PMN-platelet cooperation significantly worsens reperfusion injury (10).
The vasoactive effect of PAF and its PMN-dependent
mechanism have been directly studied in coronary resistance vessels using an isolated and perfused microvessel
preparation (190). In this study topical application of PAF
to the vessels induced a dose-dependent decrease in the
diameter but an increase in the apparent permeability
coefficient of albumin. Disruption of the endothelium
abolished the vasomotor response to PAF, and perfusion
of PMN significantly augmented PAF-induced changes in
vasomotor tone and permeability. Furthermore, administration of PAF caused PMN adhesion to the endothelium
of coronary arterioles at low-flow perfusion velocities.
These results suggest that PAF induces vasoconstriction
and hyperpermeability in coronary arterioles via an endothelium-dependent and PMN-mediated mechanism and
that PAF is able to stimulate PMN adhesion in coronary
arterioles under a condition of low flow rate (190). Moreover, a link exists between the well-established role of
oxygen radicals and that of PAF in ischemia reperfusion
injury. In fact, it was found that generation of oxygen
1685
radicals stimulates the synthesis of PAF by endothelium
in isolated perfused guinea pig heart and that a PAF
receptor antagonist blunts the mechanical and electrical
alterations induced by oxygen radicals (9). Additional
support for the role of PAF in myocardial ischemia was
obtained in experiments of PAF administration after induction of cardiac ischemia (250, 283, 393). In this experimental condition, the infusion of PAF significantly enhanced the ischemic injury by a mechanism dependent on
thromboxane A2 generation (283). Finally, the effect of
PAF receptor antagonists was studied in four experimental conditions: 1) the isolated perfused heart under conditions of ischemia followed by reperfusion, 2) the experimental myocardial infarction by coronary occlusion and
reperfusion, 3) in a model of low-flow high-demand ischemia and reperfusion (366), and 4) in the cyclic constriction of a coronary artery to mimic the clinical situation of
unstable angina. In the isolated perfused heart, PAF antagonists prevented both the platelet-dependent and
platelet-independent mechanical and electrical alterations that occurred, respectively, in rabbit (10, 34, 291),
guinea pig (141), and rat heart (127, 221, 222) after ischemia-reperfusion. In the experimental myocardial infarction by coronary occlusion, PAF receptor antagonists reduced the hematological and hemodynamic alterations as
well as the size of necrotic area and the accumulation of
platelets and leukocytes observed in rabbit (287, 288) and
sheep (213) hearts but did not affect plasma protein leakage (91, 287, 459). In rats, PAF antagonists reduced infarct
size and arrhythmias (144, 158, 263, 265). In dogs, conflicting results were obtained with different PAF receptor
antagonists. With the use of BN 52021, SRI 63441, and
TCV-309, a protective effect was observed (156, 267–270,
408), whereas WEB 2086 was uneffective (248, 249).
Moreover, it was found that CV 6209 prevented pulmonary edema following coronary ligation in dogs (409).
With the use of PAF antagonists in the cyclic constriction
of a coronary artery to mimic the clinical situation of
unstable angina, it was found that PAF contribute to
platelet activation involved in the cyclic flow variations at
the site of arterial stenosis and endothelial injury (151). It
was shown that the cyclic flow variations depend on the
release of mediators from platelets (18). In humans, an
increase of PAF concentration in blood was observed in
patients with defined unstable angina (371). Moreover,
acute myocardial infarction is associated with a depression of plasma acetyl hydrolase activity that may allow a
prolonged half-life of newly synthesized PAF (316, 400).
Plateles from patients with acute myocardial infarction
exhibit an increased sensitivity to the aggregatory effect
of PAF in vitro in the first 48 h after the onset of the
symptoms (431). We (293) and Graham et al. (154) were
unable to find an increased synthesis of PAF in peripheral
blood of patients with myocardial infarction. Whether a
local synthesis of PAF occurs is unknown. However, suc-
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MONTRUCCHIO, ALLOATTI, AND CAMUSSI
cessful thrombolytic therapy with streptokinase was associated with intravascular release of PAF. Streptokinase
as well as plasmin were shown to stimulate PAF synthesis
by endothelium, an event that may limit the beneficial
effect of thrombolytic therapy by promoting platelet and
leukocyte adhesion and activation on the endothelial cell
surface as well as transmigration into ischemic tissue
(289, 293, 298). Indeed, it has been shown that PAF receptor antagonists prevent thrombotic reocclusion in
dogs treated with recombinant-tissue-type plasminogen
activator (421). Moreover, blockade of PAF receptors
abrogated hypotension and platelet activation in rabbits
treated with streptokinase and recombinant-tissue-type
plasminogen activator (289).
Recently, it has been reported that PAF released
during angioplasty in humans (123) mediates the neutrophil stimulation seen in this clinical setting (377, 378).
C. Role of PAF in Atherogenesis
PAF may play a role in atherogenesis and atherosclerosis (183, 402). The possible involvement of PAF in cholesterol deposition in the arterial wall has been investigated in rabbits fed a hypercholesterolemic diet (131).
The administration of a PAF receptor antagonist to these
rabbits significantly reduced the amount of estherified
cholesterol in the aorta without affecting the plasma levels of cholesterol (131). Clinical studies show higher levels of PAF in coronary artery samples from patients with
severe atherosclerosis (302). It has been suggested that
PAF synthesized by endothelial cells and exposed on the
cell surface may, together with P selectin, promote leukocyte adhesion to endothelial cells (479, 480). This interaction may be important for the activation and the
subsequent infiltration of monocytes-macrophages, for
the production of proliferative cytokines, and eventually
for the accumulation of lipids within the cells (355). It has
been shown that PAF and P-selectin cooperate in the
nuclear translocation of a transcription factor NF␬B and
in the secretion of NF␬B-dependent cytokines by monocytes. PAF has a weak agonist effect for NF␬B-dependent
actions in nonadherent monocytes (456). In contrast, the
adhesion to P-selectin expressed on the endothelial surface amplifies or integrates signals triggered by PAF receptor, leading to the activation of NF␬B-dependent functions (224, 455, 456). Furthermore, PAF stimulates, in
monocytes, transcription of a heparin binding epidermal
growth factor, and in vascular smooth muscle, synthesis
of IL-6 that may act as potent mitogen for vascular smooth
muscle cells (146, 329). Moreover, it has been shown that
PAF mediates at least in part the adhesion of monocytes
to endothelium induced by LDL and oxydized LDL (246).
Cigarette smoking, a factor associated with the pathogenesis of atherosclerosis, causes platelet activation, LDL
Volume 80
oxidative changes, and increased levels of PAF (285). The
latter alteration was associated with a compensatory increase of PAF-AH activity. However, in vitro studies demonstrated that cigarette-derived products as well as oxidative changes of LDL, that physiologically carry PAF
specific acetyl hydrolase, inhibit the activity of the enzyme that catabolizes PAF (285). Furthermore, PAF may
also oxidize LDL, via stimulation of human monocytes/
macrophages and neutrophils to produce superoxide anions and hydrogen peroxide (356, 419). PAF may also
induce a release of proteases such as elastase from leukocytes that may degradate components of the extracellular matrix of the intima (356). This may favor the fissuration of the plaque (256). Indeed, an enhanced
concentration of PAF was detected in endarterectomy
samples of patients with complicated coronary plaques
(302). It has been also shown that PAF is transiently
produced by macrophages and cholesterol-loaded macrophage foam cells activated by phagocytosis, suggesting
that PAF of macrophage origin may exert potent proinflammatory, proatherogenic, and prothrombotic effects
(114).
X. ROLE OF PLATELET-ACTIVATING FACTOR
IN NEOANGIOGENESIS
Neoangiogenesis has an important role in the embryogenesis of the heart and in the repair of myocardial
infarction. The angiogenic process is, in physiological
conditions, highly regulated to direct the organ development or to limit the growth of new blood vessels to the
repaired tissue. An unregulated growth of blood vessels
may be involved in pathological processes such as
chronic inflammation, rupture of coronary plaques and
intraplaque hemorrhage, and growth of most solid tumors
(142, 143). In these conditions, angiogenesis may contribute to the development of tissue injury. Several angiogenic factors have been shown to modulate angiogenesis
(142, 143). Endothelial cells are the primary target for
these mediators and are stimulated to degradate extracellular matrix, migrate, and proliferate. These events are
required to initiate a capillary sprout and the formation of
new vessels. In this complex process, endothelium is
actively involved and is capable of producing autocrine
mediators such as the vascular endothelial growth factor
(142, 143) and IL-8 (216). The relevance of angiogenesis in
the recovery from myocardial infarction is supported by
the recent observations that the administration of basic
fibroblast growth factor and heparin significantly improves the collateral formation (169, 237, 342, 433). There
is evidence indicating that PAF may act as a mediator of
angiogenesis (15, 16, 59, 76, 295). Whereas in vitro PAF
has only a chemotactic effect on endothelial cells but
does not stimulate endothelial cell proliferation (76), in
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PAF AND THE CARDIOVASCULAR SYSTEM
1687
vivo PAF can induce an angiogenic response. The angiogenic effect of PAF is either a heparin-independent or
heparin-dependent mechanism according to concentration (76). At micromolar concentrations, PAF induces an
angiogenesis independent from addition of exogenous
heparin, possibly because the inflammatory reaction elicited may determine heparin release from mastocytes and
endothelial cells (15, 16). In contrast, at nanomolar concentrations, PAF requires the addition of exogenous heparin for its angiogenic activity, suggesting the production
of heparin binding growth factors (59, 76). PAF may directly provide the signal for migration but not the signal
for endothelial cell proliferation, which is induced by
heparin-binding growth factors, produced by PAF-stimulated endothelial cells. Indeed, PAF induced the expression of several angiogenic factors and chemokines including acid and basic fibroblast growth factor, vascular
endothelial growth factor and its specific receptor flk-1,
hepatocyte growth factor, and macrophage inflammatory
protein 2 (59, 475). Moreover, we recently observed that
PAF-induced neoangiogenesis was dependent on the production of nitric oxide (297). In vivo and in vitro experiments, performed with a panel of different PAF receptor
antagonists, suggest that the synthesis of PAF induced by
several polypeptide mediators, such as TNF-␣, hepatocyte
growth factor, VEGF, thrombopoietin, and IL-3, accounts
for the endothelial migration required for the development of the new vessels (53, 77, 115, 295, 296). In contrast,
the neoangiogenic effect of basic fibroblast growth factor
appears to be independent from the expression of the
PAF bioactivity (297).
the physiological modulation of blood pressure, mainly by
affecting the renal vascular circulation. However, most of
the available studies have been performed using nanomolar concentration of the mediator, which are reached only
in physiopathological conditions. In the cardiovascular
system, PAF has been involved in the hypotension and
cardiac dysfunctions occurring in cardiac anaphylaxis
and in various cardiovascular stress situations such as
septic, hemorragic, and traumatic shocks. Moreover, PAF
cooperate in the recruitment of leukocytes in inflamed
tissue, promoting the activation of cells ensuing in adhesion to the endothelium and extravascular transmigration
of leukocytes. The autocrine and paracrine effects of PAF
are also involved in the enhancement of endothelial cell
permeability and regulation of macro- and microvascular
tone. Moreover, the angiogenic properties of PAF may
contribute either to the development of chronic inflammatory angiogenesis or to restoration of the collateral
blood flow in ischemic tissue. The finding that PAF is
present in complicated atherosclerotic plaques, where
neoangiogenesis has been implicated in the fissuration,
suggests that PAF may have a role in the evolution of
atherosclerotic lesion. Finally, studies based on measurement of the local production of PAF and on the action of
PAF receptor antagonists have indicated that this mediator is critical in the development of myocardial ischemiareperfusion injury and of adverse effects of thrombolytic
therapy. In particular, the finding that the human heart
can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that
this mediator may have a role in a local response of the
heart to injury.
XI. CONCLUSIONS
This work was supported by the National Research Council
(Consiglio Nazionale delle Ricerche), Targeted Project “Biotechnology,” and by Ministero dell’Universitá della Ricerca Scientifica e Technologica cofin98 (to G. Camussi).
Address for reprint requests and other correspondence: G.
Camussi, Laboratorio di Immunopatologia, Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S.
Giovanni Battista, Corso Dogliotti, 14, 10126 Torino, Italy (Email: giovanni.camussi@unito.it).
Despite growing evidence indicating a role of PAF in
several pathological conditions, this mediator is still in
search of a defined physiological role. The main difficulties in studying the physiological functions of PAF are
related to technical hindrance in dosing the mediator,
which in normal cells and tissues is synthesized in picomolar concentrations. Significant progress was achieved
after cloning the receptor and the main catabolic enzyme
PAF-AH. Moreover, functional information was derived
from the use of several chemically unrelated PAF receptor antagonists. The in vitro studies provided evidence for
a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. Triggering
of PAF receptors was shown to elicit different responses,
depending on cell type, PAF concentration, and cooperation with other intercellular mediators or intracellular
messengers. In the cardiovascular system, PAF may have
a role in embryogenesis, because it possesses angiogenic
properties and acts by amplifying the effect of defined
polypeptide mediators. PAF has been also implicated in
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